AHA inotropes and vasopressors review 2008 khotailieu y hoc

Inotropes and Vasopressors: Review of Physiology and Clinical Use in Cardiovascular
Disease
Christopher B. Overgaard and Vladimír Dzavík
Circulation. 2008;118:1047-1056
doi: 10.1161/CIRCULATIONAHA.107.728840
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2008 American Heart Association, Inc. All rights reserved.
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Contemporary Reviews in Cardiovascular Medicine
Inotropes and Vasopressors
Review of Physiology and Clinical Use in Cardiovascular Disease
Christopher B. Overgaard, MD; Vladimír Dzˇavík, MD

I

notropic and vasopressor agents have increasingly become

a therapeutic cornerstone for the management of several
important cardiovascular syndromes. In broad terms, these
substances have excitatory and inhibitory actions on the heart
and vascular smooth muscle, as well as important metabolic,
central nervous system, and presynaptic autonomic nervous
system effects. They are generally administered with the
assumption that short- to medium-term clinical recovery will
be facilitated by enhancement of cardiac output (CO) or
vascular tone that has been severely compromised by often
life-threatening clinical conditions. The clinical efficacy of
these agents has been investigated largely through examination of their impact on hemodynamic end points, and clinical
practice has been driven in part by expert opinion, extrapolation from animal studies, and physician preference. Our aim
is to review the mechanisms of action of common inotropes
and vasopressors and to examine the contemporary evidence
for their use in important cardiac conditions.

Cardiovascular Effects of Common Inotropes
and Vasopressors
Catecholamines
Since the initial discovery of epinephrine, the principal active
substance from the adrenal gland,1 the pharmacology and
physiology of a large group of endogenous and synthetic
catecholamines or “sympathomimetics” have been characterized.2 Catecholamines mediate their cardiovascular actions
predominantly through ␣1, ␤1, ␤2, and dopaminergic receptors, the density and proportion of which modulate the
physiological responses of inotropes and pressors in individual tissues. ␤1-Adrenergic receptor stimulation results in
enhanced myocardial contractility through Ca2ϩ-mediated
facilitation of the actin-myosin complex binding with troponin C and enhanced chronicity through Ca2ϩ channel activation (Figure 1). ␤2-Adrenergic receptor stimulation on vascular smooth muscle cells through a different intracellular
mechanism results in increased Ca2ϩ uptake by the sarcoplasmic reticulum and vasodilation (Figure 1). Activation of
␣1-adrenergic receptors on arterial vascular smooth muscle
cells results in smooth muscle contraction and an increase in

systemic vascular resistance (SVR; Figure 2). Finally, stimulation of D1 and D2 dopaminergic receptors in the kidney and

splanchnic vasculature results in renal and mesenteric vasodilation through activation of complex second-messenger
systems.
A continuum exists between the effects of the predominantly ␣1-stimulation of phenylephrine (intense vasoconstriction) to the ␤-stimulation of isoproterenol (marked increase in
contractility and heart rate; Table). Specific cardiovascular
responses are further modified by reflexive autonomic
changes after acute blood pressure alterations, which impact
heart rate, SVR, and other hemodynamic parameters. Adrenergic receptors can be desensitized and downregulated in
certain conditions, such as in chronic heart failure (HF).4
Finally, the relative binding affinities of individual inotropes
and vasopressors to adrenergic receptors can be altered by
hypoxia5 or acidosis,6 which mutes their clinical effect.
Dopamine
Dopamine, an endogenous central neurotransmitter, is the
immediate precursor to norepinephrine in the catecholamine
synthetic pathway (Figure 3A). When administered therapeutically, it acts on dopaminergic and adrenergic receptors to
elicit a multitude of clinical effects (Table). At low doses (0.5
to 3 ␮g ⅐ kgϪ1 ⅐ minϪ1), stimulation of dopaminergic D1
postsynaptic receptors concentrated in the coronary, renal,
mesenteric, and cerebral beds and D2 presynaptic receptors
present in the vasculature and renal tissues promotes vasodilation and increased blood flow to these tissues. Dopamine
also has direct natriuretic effects through its action on renal
tubules.7 The clinical significance of “renal-dose” dopamine
is somewhat controversial, however, because it does not
increase glomerular filtration rate, and a renal protective
effect has not been demonstrated.8 At intermediate doses (3 to
10 ␮g ⅐ kgϪ1 ⅐ minϪ1), dopamine weakly binds to ␤1adrenergic receptors, promoting norepinephrine release and
inhibiting reuptake in presynaptic sympathetic nerve terminals, which results in increased cardiac contractility and
chronotropy, with a mild increase in SVR. At higher infusion

rates (10 to 20 ␮g ⅐ kgϪ1 ⅐ minϪ1), ␣1-adrenergic receptor–
mediated vasoconstriction dominates.
Dobutamine
Dobutamine is a synthetic catecholamine with a strong
affinity for both ␤1- and ␤2-receptors, which it binds to at a
3:1 ratio (Table; Figure 3B). With its cardiac ␤1-stimulatory

From the Division of Cardiology, Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Correspondence to Dr Vladimír Dzˇavík, Division of Cardiology, Toronto General Hospital, 200 Elizabeth St, EN6-246, Toronto, Ontario, Canada M5G
2C4. E-mail
(Circulation. 2008;118:1047-1056)
© 2008 American Heart Association, Inc.
Circulation is available at

DOI: 10.1161/CIRCULATIONAHA.107.728840

1047
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1048

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September 2, 2008

β agonist

α agonist

β receptor

cell membrane

α1 receptor

cell membrane

↑ Gs-GTP
+

+

Ca2+ channel
activation

+

↑ cAMP

+
+

cAMP-dependent
protein kinase
↑ phosphorylated
phospholamban

↑ cytosolic Ca2+
+

+

augmented Ca2+
uptake by SR

actin-myosin-troponin
interaction
POSITIVE
CHRONOTROPY

Gq

adenyl cyclase

POSITIVE
INOTROPY

VASODILATION

Figure 1. Simplified schematic of postulated intracellular actions
of ␤-adrenergic agonists. ␤-Receptor stimulation, through a
stimulatory Gs-GTP unit, activates the adenyl cyclase system,
which results in increased concentrations of cAMP. In cardiac
myocytes, ␤1-receptor activation through increased cAMP concentration activates Ca2ϩ channels, which leads to Ca2ϩmediated enhanced chronotropic responses and positive inotropy by increasing the contractility of the actin-myosin-troponin
system. In vascular smooth muscle, ␤2-stimulation and
increased cAMP results in stimulation of a cAMP-dependent
protein kinase, phosphorylation of phospholamban, and augmented Ca2ϩ uptake by the sarcoplasmic reticulum (SR), which
leads to vasodilation. Adapted from Gillies et al3 with permission
of the publisher.

effects, dobutamine is a potent inotrope, with weaker
chronotropic activity. Vascular smooth muscle binding
results in combined ␣1-adrenergic agonism and antagonism, as well as ␤2-stimulation, such that the net vascular
effect is often mild vasodilation, particularly at lower
doses (Յ5 ␮g ⅐ kgϪ1 ⅐ minϪ1). Doses up to 15 ␮g · kgϪ1 · minϪ1
increase cardiac contractility without greatly affecting peripheral resistance, likely owing to the counterbalancing effects of
␣1-mediated vasoconstriction and ␤2-mediated vasodilation.
Vasoconstriction progressively dominates at higher infusion
rates.9
Despite its mild chronotropic effects at low to medium
doses, dobutamine significantly increases myocardial oxygen
consumption. This exercise-mimicking phenomenon is the
basis upon which dobutamine may be used as a pharmacological stress agent for diagnostic perfusion imaging,10 but
conversely, it may limit its utility in clinical conditions in
which induction of ischemia is potentially harmful. Tolerance
can develop after just a few days of therapy,11 and malignant
ventricular arrhythmias can be observed at any dose.
Norepinephrine
Norepinephrine, the major endogenous neurotransmitter liberated by postganglionic adrenergic nerves (Table; Figure
3A), is a potent ␣1-adrenergic receptor agonist with modest
␤-agonist activity, which renders it a powerful vasoconstrictor with less potent direct inotropic properties. Norepinephrine primarily increases systolic, diastolic, and pulse pressure
and has a minimal net impact on CO. Furthermore, this agent
has minimal chronotropic effects, which makes it attractive

phospholipase C

PiP2

DAG

+

↑ IP3

+

+

↑ cytosolic Ca2+

+

protein kinase C

+

calmodulin-dependent
protein kinase
+

VASOCONSTRICTION
Figure 2. Schematic representation of postulated mechanisms
of intracellular action of ␣1-adrenergic agonists. ␣1-Receptor
stimulation activates a different regulatory G protein (Gq), which
acts through the phospholipase C system and the production of
1,2-diacylglycerol (DAG) and, via phosphatidyl-inositol-4,5biphosphate (PiP2), of inositol 1,4,5-triphosphate (IP3). IP3 activates the release of Ca2ϩ from the sarcoplasmic reticulum (SR),
which by itself and through Ca2ϩ-calmodulin– dependent protein
kinases influences cellular processes, leading in vascular
smooth muscle to vasoconstriction. Adapted from Gillies et al3

with permission of the publisher.

for use in settings in which heart rate stimulation may be
undesirable. Coronary flow is increased owing to elevated
diastolic blood pressure and indirect stimulation of cardiomyocytes, which release local vasodilators.12 Prolonged norepinephrine infusion can have a direct toxic effect on cardiac
myocytes by inducing apoptosis via protein kinase A activation and increased cytosolic Ca2ϩ influx.13
Epinephrine
Epinephrine is an endogenous catecholamine with high affinity for ␤1-, ␤2-, and ␣1-receptors present in cardiac and
vascular smooth muscle (Figure 3A; Table). ␤-Adrenergic
effects are more pronounced at low doses and ␣1-adrenergic
effects at higher doses. Coronary blood flow is enhanced
through an increased relative duration of diastole at higher
heart rates and through stimulation of myocytes to release
local vasodilators, which largely counterbalance direct ␣1mediated coronary vasoconstriction.14 Arterial and venous
pulmonary pressures are increased through direct pulmonary
vasoconstriction and increased pulmonary blood flow. High
and prolonged doses can cause direct cardiac toxicity through
damage to arterial walls, which causes focal regions of
myocardial contraction band necrosis, and through direct
stimulation of myocyte apoptosis.15
Isoproterenol
Isoproterenol is a potent, nonselective, synthetic ␤-adrenergic
agonist with very low affinity for ␣-adrenergic receptors

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Overgaard and Dzˇavík

Inotropes, Vasopressors, and Cardiovascular Disease

1049

Table. Inotropic and Vasopressor Drug Names, Clinical Indication for Therapeutic Use, Standard Dose Range, Receptor Binding
(Catecholamines), and Major Clinical Side Effects
Receptor Binding
Clinical Indication

Dose Range

␣1

␤1

␤2

DA

Major Side Effects

Shock (cardiogenic, vasodilatory)
HF
Symptomatic bradycardia
unresponsive to atropine or
pacing

2.0 to 20 ␮g ⅐ kgϪ1 ⅐ minϪ1
(max 50 ␮g ⅐ kgϪ1 ⅐ minϪ1)

ϩϩϩ

ϩϩϩϩ

ϩϩ

ϩϩϩϩϩ

Severe hypertension (especially in
patients taking nonselective
␤-blockers)
Ventricular arrhythmias
Cardiac ischemia
Tissue ischemia/gangrene (high doses
or due to tissue extravasation)

Low CO (decompensated HF,
cardiogenic shock,
sepsis-induced myocardial
dysfunction)
Symptomatic bradycardia
unresponsive to atropine or
pacing

2.0 to 20 ␮g ⅐ kgϪ1 ⅐ minϪ1
(max 40 ␮g ⅐ kgϪ1 ⅐ minϪ1)

ϩ

ϩϩϩϩϩ

ϩϩϩ

N/A

Tachycardia
Increased ventricular response rate in
patients with atrial fibrillation
Ventricular arrhythmias
Cardiac ischemia
Hypertension (especially nonselective
␤-blocker patients)
Hypotension

Norepinephrine

Shock (vasodilatory, cardiogenic)

0.01 to 3 ␮g ⅐ kgϪ1 ⅐ minϪ1

ϩϩϩϩϩ

ϩϩϩ

ϩϩ

N/A

Arrhythmias
Bradycardia
Peripheral (digital) ischemia

Hypertension (especially nonselective
␤-blocker patients)

Epinephrine

Shock (cardiogenic, vasodilatory)
Cardiac arrest
Bronchospasm/anaphylaxis
Symptomatic bradycardia or
heart block unresponsive to
atropine or pacing

Infusion: 0.01 to 0.10
␮g ⅐ kgϪ1 ⅐ minϪ1
Bolus: 1 mg IV every 3 to 5
min (max 0.2 mg/kg)
IM: (1:1000): 0.1 to 0.5 mg
(max 1 mg)

ϩϩϩϩϩ

ϩϩϩϩ

ϩϩϩ

N/A

Ventricular arrhythmias
Severe hypertension resulting in
cerebrovascular hemorrhage

Cardiac ischemia
Sudden cardiac death

Isoproterenol

Bradyarrhythmias (especially
torsade des pointes)
Brugada syndrome

2 to 10 ␮g/min

0

ϩϩϩϩϩ

ϩϩϩϩϩ

N/A

Ventricular arrhythmias
Cardiac ischemia
Hypertension
Hypotension

Phenylephrine

Hypotension (vagally mediated,
medication-induced)
Increase MAP with AS and
hypotension

Decrease LVOT gradient in HCM

Bolus: 0.1 to 0.5 mg IV
every 10 to 15 min
Infusion: 0.4 to 9.1
␮g ⅐ kgϪ1 ⅐ minϪ1

ϩϩϩϩϩ

0

0

N/A

Reflex bradycardia
Hypertension (especially with
nonselective ␤-blockers)
Severe peripheral and visceral
vasoconstriction
Tissue necrosis with extravasation

Milrinone

Low CO (decompensated HF,
after cardiotomy)

Bolus: 50 ␮g/kg bolus over
10 to 30 min
Infusion: 0.375 to 0.75

␮g ⅐ kgϪ1 ⅐ minϪ1 (dose
adjustment necessary for
renal impairment)

N/A

Ventricular arrhythmias
Hypotension
Cardiac ischemia
Torsade des pointes

Amrinone

Low CO (refractory HF)

Bolus: 0.75 mg/kg over 2
to 3 min
Infusion: 5 to 10
␮g ⅐ kgϪ1 ⅐ minϪ1

N/A

Arrhythmias, enhanced AV conduction
(increased ventricular response rate in
atrial fibrillation)
Hypotension
Thrombocytopenia
Hepatotoxicity

Shock (vasodilatory, cardiogenic)

Cardiac arrest

Infusion: 0.01 to 0.1 U/min
(common fixed dose 0.04
U/min)
Bolus: 40-U IV bolus

V1 receptors (vascular smooth muscle)
V2 receptors (renal collecting duct system)

Arrhythmias
Hypertension
Decreased CO (at doses Ͼ0.4 U/min)
Cardiac ischemia
Severe peripheral vasoconstriction
causing ischemia (especially skin)
Splanchnic vasoconstriction

Decompensated HF

Loading dose: 12 to 24
␮g/kg over 10 min
Infusion: 0.05 to 0.2
␮g ⅐ kgϪ1 ⅐ minϪ1

N/A

Tachycardia, enhanced AV conduction
Hypotension

Drug
Catecholamines
Dopamine

Dobutamine

PDIs

Vasopressin

Levosimendan

␣1 indicates ␣-1 receptor; ␤1, ␤-1 receptor; ␤2, ␤-2 receptor; DA, dopamine receptors; 0, zero significant receptor affinity; ϩ through ϩϩϩϩϩ, minimal to
maximal relative receptor affinity; N/A, not applicable; IV, intravenous; IM, intramuscular; max, maximum; AS, aortic stenosis; LVOT, LV outflow tract; HCM,
hypertrophic cardiomyopathy; and AV, atrioventricular.

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A

B
O

HO

OH

N

Dobutamine

Phenylalanine

NH2

CH3

HO

HO
Phenylalanine
hydroxylase

O

OH
HO

OH
HO

CH3

N

Tyrosine

NH2

Tyrosine hydroxylase
tetrahydrobiopterin

O

Isoproterenol

CH3
HO

HO

L-Dopa

OH

OH

NH2

HO
Dopa decarboxylase
pyridoxal phosphate

HO
HO

NH2

Phenylephrine
CH3

Dopamine
Dopamine

HO

β-hydroxylase

OH
HO

ascorbate

NH2

Norepinephrine
PhenylethanolamineN-methyltransferase
S-adenosylmethionine

HO
OH
HO

N

NHCH3

Epinephrine

HO
Figure 3. A, Endogenous catecholamine synthesis pathway. Left, chemical structures; Right, names of compounds with conversion
enzymes (italics) and cofactors (bold). B, Chemical structures and names of common synthesized catecholamines.

(Table; Figure 3B). It has powerful chronotropic and inotropic properties, with potent systemic and mild pulmonary
vasodilatory effects. Its stimulatory impact on stroke volume
is counterbalanced by a ␤2-mediated drop in SVR, which
results in a net neutral impact on CO.
Phenylephrine
With its potent synthetic ␣-adrenergic activity and virtually
no affinity for ␤-adrenergic receptors (Table; Figure 3B),
phenylephrine is used primarily as a rapid bolus for immediate correction of sudden severe hypotension. It can be used to
raise mean arterial pressure (MAP) in patients with severe
hypotension and concomitant aortic stenosis, to correct hypotension caused by the simultaneous ingestion of sildenafil
and nitrates, to decrease the outflow tract gradient in patients
with obstructive hypertrophic cardiomyopathy, and to correct
vagally mediated hypotension during percutaneous diagnostic
or therapeutic procedures. This agent has virtually no direct
heart rate effects, although it has the potential to induce
significant baroreceptor-mediated reflex rate responses after
rapid alterations in MAP.

Phosphodiesterase Inhibitors
Phosphodiesterase 3 is an intracellular enzyme associated

with the sarcoplasmic reticulum in cardiac myocytes and

vascular smooth muscle that breaks down cAMP into AMP.
Phosphodiesterase inhibitors (PDIs) increase the level of
cAMP by inhibiting its breakdown within the cell, which
leads to increased myocardial contractility (Figure 4). These
agents are potent inotropes and vasodilators and also improve
β agonist
β receptor
cell membrane
↑ Gs-GTP
+

adenyl cyclase
ATP

↑ cAMP

Phosphodiesterase
_
Inhibitors

PDE3

AMP

Figure 4. Basic mechanism of action of PDIs. PDIs lead to
increased intracellular concentration of cAMP, which increases
contractility in the myocardium and leads to vasodilation in vascular smooth muscle.

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Inotropes, Vasopressors, and Cardiovascular Disease

diastolic relaxation (lusitropy), thus reducing preload, afterload, and SVR.
Milrinone is the PDI most commonly used for cardiovascular indications (Table). In its parenteral form, it has a longer
half-life (2 to 4 hours) than many other inotropic medications.
This drug is particularly useful if adrenergic receptors are
downregulated or desensitized in the setting of chronic HF, or
after chronic ␤-agonist administration. Amrinone is used less
often because of important side effects, which include doserelated thrombocytopenia.

Vasopressin
Isolated in 1951,16 the nonapeptide vasopressin or “antidiuretic hormone” is stored primarily in granules in the posterior pituitary gland and is released after increased plasma
osmolality or hypotension, as well as pain, nausea, and
hypoxia. Vasopressin is synthesized to a lesser degree by the
heart in response to elevated cardiac wall stress17 and by the
adrenal gland in response to increased catecholamine secretion.18 It exerts its circulatory effects through V1 (V1a in
vascular smooth muscle, V1b in the pituitary gland) and V2
receptors (renal collecting duct system; Table). V1a stimulation mediates constriction of vascular smooth muscle,
whereas V2 receptors mediate water reabsorption by enhancing renal collecting duct permeability.
Vasopressin causes less direct coronary and cerebral vasoconstriction than catecholamines and has a neutral or inhibitory impact on CO, depending on its dose-dependent increase in SVR and the reflexive increase in vagal tone. A
vasopressin-modulated increase in vascular sensitivity to
norepinephrine further augments its pressor effects. The agent
may also directly influence mechanisms involved in the
pathogenesis of vasodilation, through inhibition of ATP-activated potassium channels,19 attenuation of nitric oxide
production,20 and reversal of adrenergic receptor downregulation.21 The pressor effects of vasopressin are relatively

preserved during hypoxic and acidotic conditions, which
commonly develop during shock of any origin.

Calcium-Sensitizing Agents
Calcium sensitizers are a recently developed class of
inotropic agents, levosimendan being the most well known
(Table).22 These agents have a dual mechanism of action that
includes calcium sensitization of contractile proteins and the
opening of ATP-dependent potassium (Kϩ) channels.
Calcium-dependent binding to troponin C enhances ventricular contractility without increasing intracellular Ca2ϩ concentration or compromising diastolic relaxation, which may
favorably impact myocardial energetics relative to traditional
inotropic therapies. The opening of Kϩ channels on vascular
smooth muscle leads to arteriolar and venous vasodilation
and may confer a degree of myocardial protection during
ischemia.23 The combination of improved contractile performance and vasodilation is particularly beneficial during acute
and chronic HF states, for which levosimendan is being used
with increasing frequency in some countries.

1051

Evidence for Use of Inotropes and
Vasopressors in Cardiovascular Disease
Cardiogenic Shock Complicating Acute
Myocardial Infarction
Inotropes and vasopressors are used routinely in the setting of
cardiogenic shock complicating acute myocardial infarction
(AMI). These agents all increase myocardial oxygen consumption and can cause ventricular arrhythmias, contractionband necrosis, and infarct expansion. However, critical hypotension itself compromises myocardial perfusion, leading
to elevated left ventricular (LV) filling pressures, increased
myocardial oxygen requirements, and further reduction in the
coronary perfusion gradient. Thus, hemodynamic benefits

usually outweigh specific risks of inotropic therapy when
used as a bridge to more definitive treatment measures.
Inotropic agents may improve mitochondrial function in
noninfarcted myocardium that has become deranged during
AMI complicated by shock.24 However, free cytosolic Ca2ϩ,
which is significantly elevated in postischemic cardiac myocytes, is further increased with the administration of dopamine, which leads to activation of proteolytic enzymes,
proapoptotic signal cascades, mitochondrial damage, and
eventual membrane disruption and necrosis.25 Thus, the
lowest possible doses of inotropic and pressor agents should
be used to adequately support vital tissue perfusion while
limiting adverse consequences, some of which may not be
immediately apparent.
The American College of Cardiology/American Heart
Association guidelines for management of hypotension complicating AMI suggest the use of dobutamine as a first-line
agent if systolic blood pressure ranges between 70 and
100 mm Hg in the absence of signs and symptoms of shock.
Dopamine is suggested in patients who have the same systolic
blood pressure in the presence of symptoms of shock.26
However, definitive evidence supporting use of specific
agents in this setting is lacking. Moderate doses of these
agents maximize inotropy and avoid excessive ␣1-adrenergic
stimulation that can result in end-organ ischemia. The deliberate combination of dopamine and dobutamine at a dose of
7.5 ␮g ⅐ kgϪ1 ⅐ minϪ1 each was shown to improve hemodynamics and limit important side effects compared with either
individual agent administered at 15 ␮g ⅐ kgϪ1 ⅐ minϪ1.27 Moderate doses of combinations of medications may potentially
be more effective than maximal doses of any individual
agent.
When response to a medium dose of dopamine or dopamine/dobutamine in combination is inadequate, or the patient’s presenting systolic blood pressure is Ͻ70 mm Hg, the
use of norepinephrine has been recommended.26 With an
antithrombotic effect in addition to its pressor qualities,
norepinephrine may be the optimal choice under these conditions compared with epinephrine, which can exacerbate

lactic acidosis and promote thrombosis in coronary
vasculature.28
During early shock, endogenous vasopressin levels are
elevated significantly to help maintain end-organ perfusion.29
As the shock state progresses, however, plasma vasopressin
levels fall dramatically, which contributes to a loss of

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vascular tone, worsening hypotension, and end-organ perfusion. Proposed mechanisms to explain this phenomenon
include depletion of neurohypophyseal stores,30 baroreceptor
and generalized autonomic dysfunction during prolonged
shock,31 and endogenous norepinephrine-induced inhibition
of vasopressin release.32 Vasopressin therapy may thus be
effective in norepinephrine-resistant vasodilatory shock, improving MAP, cardiac index, and LV stroke work index and
reducing the need for norepinephrine, resulting in decreased
cardiotoxicity and malignant arrhythmias.33 Vasopressin may
also attenuate interleukin-induced generation of nitric oxide,
have a modest inotropic effect on the myocardium via
V1a-mediated increases in intracellular Ca2ϩ, and improve
coronary blood flow due to catecholamine sparing.34
In the only study to date that examined vasopressin use in
cardiogenic shock after AMI, this agent was found to increase

MAP without adversely impacting cardiac index and wedge
pressure.35 Cardiac power index, an important determinant of
outcome in cardiogenic shock after AMI, was not adversely
affected by vasopressin but decreased when norepinephrine
was used. Further studies to validate the use of vasopressin in
this setting are needed.

Congestive HF
Inotropic therapy is used in the management of decompensated HF to lower end-diastolic pressure and improve diuresis, thus allowing traditional medical therapy (eg, angiotensin-converting enzyme inhibitors, diuretics, and ␤-blockers)
to be reinstituted gradually. Patients with decompensated HF
unresponsive to diuresis often have diminished concomitant
peripheral perfusion, clinically apparent as cool extremities,
narrowed pulse pressure, and worsening renal function. They
may have markedly elevated SVR despite hypotension due to
the stimulation of the renal-angiotensin-aldosterone system,
as well as release of endogenous catecholamines and vasopressin. In this setting, reversal of systemic vasoconstriction
is often achieved through the use of vasodilators (such as
sodium nitroprusside) and inotropes with peripheral vasodilatory properties to improve hemodynamic parameters and
clinical symptoms.
The use of positive inotropes (parenteral inotropes and oral
PDIs) in chronic HF has been consistently demonstrated to
increase mortality.36,37 A proposed central mechanism involves a chronic increase in intracellular Ca2ϩ, which contributes to altered gene expression and apoptosis and an
increased likelihood of malignant ventricular arrhythmias.38
As a result, the current American College of Cardiology/
American Heart Association guidelines for diagnosis and
management of chronic HF in the adult do not recommend
the routine use of intravenous inotropic agents for patients
with refractory end-stage HF (class III recommendation) but
do state that they may be considered for palliation of
symptoms in these patients (class IIb recommendation).39 The

European Society of Cardiology acute HF guidelines also
stress that few controlled trials with intravenous inotropic
agents have been performed.40 However, these guidelines do
point out that in an appropriate clinical setting of hypotension
and peripheral hypoperfusion, particular agents may be indicated with slightly different levels of recommendation (do-

butamine and levosimendan, class IIa; PDIs and dopamine,
class IIb).41
The most commonly recommended initial inotropic therapies for refractory HF (dobutamine, dopamine, and milrinone) are used to improve CO and enhance diuresis by
improving renal blood flow and decreasing SVR without
exacerbating systemic hypotension. Dobutamine stimulation
of ␤1- and ␤2-receptors can achieve this goal at low to
medium doses by modestly increasing contractility with
usually mild systemic vasodilation. Unfortunately, ␤-adrenergic
receptor responses are often blunted in the failing human heart.
A chronic increase in activation of the sympathetic nervous
system and increased circulating catecholamine levels results
in a phosphorylation signal that leads to uncoupling of the
surface receptor from its intracellular signal transduction
proteins (desensitization), as well as increased receptor targeting for endocytosis (decreased receptor density).42 PDIs
such as milrinone, acting through a non–␤-adrenergic mechanism, are not associated with diminished efficacy or tolerance with prolonged use. This drug causes relatively more
significant right ventricular afterload reduction through pulmonary vasodilation and less direct cardiac inotropy, which
results in less myocardial oxygen consumption. Milrinone
can cause severe systemic hypotension, necessitating the
coadministration of additional pressor therapies. Direct randomized comparisons of milrinone and dobutamine have
been small and have demonstrated similar clinical
outcomes.43,44
Several major clinical trials have evaluated the safety and
efficacy of levosimendan in HF syndromes. Two early studies
demonstrated a mortality benefit in patients given levosimendan versus placebo early (within 14 days) in the setting of LV

failure complicating AMI (RUSSLAN [Randomized Study
on Safety and Effectiveness of Levosimendan in Patients
With Left Ventricular Failure due to an Acute Myocardial
Infarct])45 and at 180 days in the setting of chronic HF when
compared with dobutamine therapy (LIDO [Levosimendan
Infusion versus Dobutamine in Severe Low-Output Heart
Failure]).46 However, in larger multicenter randomized trials
in the setting of acute decompensated HF (REVIVE II
[Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy] and SURVIVE [Survival of Patients With
Acute Heart Failure in Need of Intravenous Inotropic Support]),47,48 levosimendan use significantly improved symptoms but not survival.
In some patients, complete inotropic dependence manifested by symptomatic hypotension, recurrent congestive
symptoms, or worsening renal function may develop after
discontinuation of parenteral therapy. Inotropic support may
become necessary until cardiac transplantation or implantation of an LV assist device can be instituted. Long-term
therapy is also used as a “bridge to decision” in patients who
are not presently destination-therapy candidates but may
become so in the future. Inotrope-dependent HF patients who
do not go on to definitive therapy have a poor prognosis, with
1-year mortality ranging from 79% to 94%.49 Long-term
inotropic therapy is associated with an increased risk of line
sepsis, arrhythmias, accelerated functional decline due to
worsening nutritional status, and direct acceleration of end-

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Inotropes, Vasopressors, and Cardiovascular Disease

organ dysfunction, such as the development of eosinophilic
myocarditis from an allergic response to chronic dobutamine
exposure.50 Inotropic home therapy has been used effectively
for palliation of symptoms in patients who are not candidates
for LV assist device support or transplantation, enabling those
individuals to die in the comfort of their own homes.51
The majority of HF patients can be weaned off inotrope
infusions successfully after diuresis of excess volume and
careful adjustment of concomitant oral medications. General
recommendations have been to keep patients in the hospital
and on a stable oral HF regimen for 48 hours before discharge
to ensure adequacy of the initiated therapy.52

Cardiopulmonary Arrest
Inotropic and vasopressor agents are a mainstay of resuscitation therapy during cardiopulmonary arrest.53 Epinephrine,
with its potent vasopressor and inotropic properties, can
rapidly increase diastolic blood pressure to facilitate coronary
perfusion and help restore organized myocardial contractility.
However, it is not clear whether epinephrine actually facilitates cardioversion to normal rhythm, and its use has been
associated with increased oxygen consumption, ventricular
arrhythmias, and myocardial dysfunction after successful
resuscitation.54 Repeated high-bolus doses (5 mg) appear no
more effective than repeated standard doses (1 mg) at
restoring circulation.55
The finding that endogenous vasopressin levels are greater
in patients successfully resuscitated from sudden cardiac
death than in nonsurvivors sparked interest in the use of
vasopressin for this indication.56 Experimentally, the use of
vasopressin during cardiopulmonary collapse has demonstrated a more beneficial effect than epinephrine on cerebral
and myocardial blood flow,57 resulting in more sustained

increases in MAP.58 Clinically, its use has been associated
with a higher rate of short-term survival in patients experiencing out-of-hospital ventricular fibrillation.59 However, in a
larger trial of 1186 patients with out-of-hospital cardiac arrest
who were randomized to 2 injections of either 40 U of
vasopressin or 1 mg of epinephrine (followed by additional
treatment with epinephrine if needed), patients with asystole
but not those with ventricular fibrillation or pulseless electrical activity were significantly more likely to survive to
hospital admission with vasopressin administration.60 The
mechanism of benefit may stem from the ability of vasopressin to retain its potent vasoconstricting properties under
severely acidotic conditions, in which catecholamines have
limited efficacy. The current American Heart Association
guidelines for adult cardiac life support have incorporated
vasopressin as a 1-time alternative to the first or second dose
of epinephrine (1-time bolus of 40 U) in patients with
pulseless electrical activity or asystole and for pulseless
ventricular tachycardia or ventricular fibrillation.53

Postoperative Cardiac Surgery
Pharmacological support may be necessary during and after
weaning from cardiopulmonary bypass in patients who have
developed a low-CO syndrome, arbitrarily defined as a
cardiac index Ͻ2.4 L · minϪ1 · mϪ2 with evidence of
end-organ dysfunction. 3 Causes of low CO include

1053

cardioplegia-induced myocardial dysfunction, precipitation
of cardiac ischemia during aortic cross-clamping, reperfusion
injury, activation of inflammatory and coagulation cascades,
and the presence of nonrepaired preexisting cardiac disease.

Therapy should be instituted promptly in addition to other
measures, including optimization of volume status, reduction
of SVR with propofol infusion, temporary pacing, and intraaortic balloon counterpulsation. Although no single agent is
universally superior in this setting, dobutamine has the most
desirable side-effect profile of the ␤-agonists, whereas PDIs
increase flow through arterial grafts, reduce MAP, and
improve right-sided heart performance in pulmonary hypertension.3 As is the case in HF, concomitant vasopressor
therapy may be necessary.
Several studies have examined the role of prophylactic
inotropic or vasopressor therapy in weaning from cardiopulmonary bypass or to improve hemodynamic status in general.
Preemptive milrinone administration before separation from
cardiopulmonary bypass was found to attenuate postoperative
deterioration in cardiac function and reduce the need for
additional inotropes.61 In off-pump bypass surgery patients,
the use of preemptive milrinone significantly ameliorates
increases in mitral regurgitation and improves hemodynamic
indexes that often deteriorate with off-pump surgery.62 Milrinone and dobutamine were both found to be effective in
improving general hemodynamic parameters compared with
placebo in a European multicenter, randomized, open-label
trial.63
The development of a systemic inflammatory response
during cardiopulmonary bypass may cause severe generalized
vasodilation, known as “vasoplegia syndrome,” which can
result in increased early mortality, especially in heart transplant recipients.64 This syndrome is associated with prolonged cardiopulmonary bypass time, orthotropic heart transplantation, and LV assist device insertion and is characterized
by severe persistent hypotension, metabolic acidosis, decreased SVR, and low intracardiac filling pressures, with
normal or elevated CO. Preoperative risk factors include
preoperative angiotensin-converting enzyme inhibitor, calcium channel blocker, or intravenous heparin use and poor
LV function.64 – 66 Development of vasoplegia syndrome may
be related to the release of vasodilatory inflammatory mediators, extensive complement activation, or vasoactive substance depletion, such as vasopressin. Although catecholamine therapy is often ineffective, methylene blue (through a
nitric oxide–inhibition mechanism) and vasopressin have

been shown to improve outcomes.65– 67

Right Ventricular Infarction
Significant right ventricular free-wall ischemia leads to immediate dilation of the right ventricle within a constrained
pericardium. A rapid increase in intrapericardial pressure and
intraventricular septal shift alters LV geometry, impairing LV
filling and contractile performance.68,69 These combined effects result in a drop in CO that may exacerbate shock.70
Excessive intravenous fluid beyond a right atrial pressure
Ͼ15 mm Hg to improve a “preload-dependent” right ventricle can result in deterioration of LV performance. Dobutamine improves myocardial performance in this setting.71

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Close observation is essential to monitor for exacerbation of
hypotension and atrial arrhythmias, which can profoundly
worsen hemodynamics.

Bradyarrhythmias

Owing to their chronotropic effects, ␤-adrenergic agonists
can be useful for transient emergency treatment of bradyarrhythmias if atropine is ineffective.53 The use of the
␤-agonists dobutamine, dopamine, or isoproterenol can stabilize the patient to allow time for a temporary pacemaker to
be inserted. These agents are also useful under the same
circumstances to treat bradycardia-induced torsade des

pointes. Finally, isoproterenol has also been used to suppress
the trigger for ventricular fibrillation in patients with the
Brugada syndrome who do not wish to have cardioverterdefibrillator implantation to prevent sudden cardiac death.72

Adjuvant Issues
Patient Monitoring During Parenteral Inotropic
and Vasopressor Therapy
Patients requiring treatment with inotropes and vasopressors
generally require monitoring in an intensive care or stepdown setting because of the potential for development of
life-threatening arrhythmias.
Invasive Blood Pressure Monitoring
In shock, continuous blood pressure monitoring with an
arterial line is essential both to monitor the status of the
underlying illness and because inotropes and vasopressors
have the potential to induce life-threatening hypotension or
hypertension. Chronic HF patients undergoing hemodynamic
tailoring with a low-dose ␤-agonist or PDI can usually be
monitored noninvasively.
Pulmonary Artery Catheter Use
Consensus on pulmonary artery catheter use during treatment
with inotropic therapy is lacking. Although this tool can be
helpful diagnostically, its routine use has never been shown to
improve outcomes.73 This may reflect an absence of effective
evidence-based therapies to be used in response to pulmonary
artery catheter data in the treatment of critically ill patients.74
In the ESCAPE trial (Evaluation Study of Congestive Heart
Failure and Pulmonary Artery Catheterization Effectiveness),
which examined pulmonary artery catheter use in patients
with severe HF, catheter insertion was deemed safe but was
not associated with improved rates of mortality or hospitalization.75 Inotropic titration with pulmonary artery catheter

data in isolation can result in inappropriate stimulation of CO,
thus negatively impacting prognosis in heterogeneous intensive care unit patient populations.76 Titration of inotropic
therapy should be guided by the adequacy of end-organ
perfusion, based on multiple clinical parameters.

Goals of Inotropic and Vasopressor Therapy
The use of inotropes and vasopressors has not been shown in
randomized, controlled studies to ultimately lead to improved
patient outcomes, at least in part because no clinical trials
have been conducted with study size and power adequate to
test their effect on improving survival. In the absence of such
data, the definitive goals of therapy must be considered of

primary importance, and the role of inotropic therapy should
be kept in a supportive context to allow treatment of the
underlying disorder. Such therapy includes prompt percutaneous or surgical revascularization and the institution of
mechanical support (intra-aortic balloon counterpulsation or
LV assist device) to improve coronary perfusion, CO, or both.

Conclusions and Recommendations
In conclusion, inotropes and vasopressors play an essential
role in the supportive care of a number of important cardiovascular disease processes. To date, prospective examination
of their impact on clinical outcomes in randomized trials has
been minimal, despite their widespread use in cardiovascular
illness. However, the recently published TRIUMPH (Tilarginine Acetate Injection in a Randomized International Study in
Unstable MI Patients With Cardiogenic Shock) international
randomized trial of NG-monomethyl L-arginine in cardiogenic
shock has shown that such trials are not only feasible but
necessary to validate findings of smaller studies.77,78 A better
understanding of the physiology and important adverse effects of these medications should lead to directed clinical use,

with realistic therapeutic goals. The following broad recommendations can be made:
Smaller combined doses of inotropes and vasopressors may
be advantageous over a single agent used at higher doses to
avoid dose-related adverse effects.
The use of vasopressin at low to moderate doses may allow
catecholamine sparing, and it may be particularly useful in
settings of catecholamine hyposensitivity and after prolonged critical illness.
In cardiogenic shock complicating AMI, current guidelines
based on expert opinion recommend dopamine or dobutamine as first-line agents with moderate hypotension (systolic blood pressure 70 to 100 mm Hg) and norepinephrine
as the preferred therapy for severe hypotension (systolic
blood pressure Ͻ70 mm Hg).
Routine inotropic use is not recommended for end-stage HF.
When such use is essential, every effort should be made to
either reinstitute stable oral therapy as quickly as possible
or use destination therapy such as cardiac transplantation
or LV assist device support.
Large randomized trials focusing on clinical outcomes are
needed to better assess the clinical efficacy of these agents.

Acknowledgments
We would like to thank Uchewnwa Genus for her assistance during
the preparation of this article.

Disclosures
Dr Overgaard is supported by a Heart and Stroke Foundation of
Canada (HSFC)/AstraZeneca Canada Inc fellowship award. Dr
Dzˇavík is supported in part by the Brompton Funds (Toronto,
Canada) Professorship in Interventional Cardiology. Dr Dzˇavík has
received research funding from Arginox Inc and speaker’s honoraria
from Datascope Inc.

References
1. Abel JJ, Taveau RD. On the decomposition products of epinephrine
hydrate. J Biol Chem. 1905;1:1–32.
2. Barger G, Dale HH. Chemical structure and sympathomimetic action of
amines. J Physiol. 1910;41:19 –59.

Downloaded from by guest on July 10, 2014


Overgaard and Dzˇavík

Inotropes, Vasopressors, and Cardiovascular Disease

3. Gillies M, Bellomo R, Doolan L, Buxton B. Bench-to-bedside review:
inotropic drug therapy after adult cardiac surgery: a systematic literature
review. Crit Care. 2005;9:266 –279.
4. Tilley DG, Rockman HA. Role of beta-adrenergic receptor signaling and
desensitization in heart failure: new concepts and prospects for treatment.
Expert Rev Cardiovasc Ther. 2006;4:417– 432.
5. Li HT, Long CS, Rokosh DG, Honbo NY, Karliner JS. Chronic hypoxia
differentially regulates ␣1-adrenergic receptor subtype mRNAs and
inhibits ␣1-adrenergic receptor-stimulated cardiac hypertrophy and signaling. Circulation. 1995;92:918 –925.
6. Modest VE, Butterworth JF IV. Effect of pH and lidocaine on betaadrenergic receptor binding: interaction during resuscitation? Chest.
1995;108:1373–1379.
7. Denton MD, Chertow GM, Brady HR. “Renal-dose” dopamine for the
treatment of acute renal failure: scientific rationale, experimental studies
and clinical trials. Kidney Int. 1996;50:4 –14.
8. Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J; Australian
and New Zealand Intensive Care Society (ANZICS) Clinical Trials

Group. Low-dose dopamine in patients with early renal dysfunction: a
placebo-controlled randomised trial. Lancet. 2000;356:2139 –2143.
9. Ruffolo RR Jr. The pharmacology of dobutamine. Am J Med Sci. 1987;
294:244 –248.
10. Patel RN, Arteaga RB, Mandawat MK, Thornton JW, Robinson VJ. Pharmacologic stress myocardial perfusion imaging. South Med J. 2007;100:
1006 –1014.
11. Unverferth DA, Blanford M, Kates RE, Leier CV. Tolerance to dobutamine after a 72 hour continuous infusion. Am J Med. 1980;69:262–266.
12. Tune JD, Richmond KN, Gorman MW, Feigl EO. Control of coronary
blood flow during exercise. Exp Biol Med (Maywood). 2002;227:
238 –250.
13. Communal C, Singh K, Pimentel DR, Colucci WS. Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the
␤-adrenergic pathway. Circulation. 1998;98:1329 –1334.
14. Jones CJ, DeFily DV, Patterson JL, Chilian WM. Endothelium-dependent
relaxation competes with ␣1- and ␣2-adrenergic constriction in the canine
epicardial coronary microcirculation. Circulation. 1993;87:1264 –1274.
15. Singh K, Xiao L, Remondino A, Sawyer DB, Colucci WS. Adrenergic
regulation of cardiac myocyte apoptosis. J Cell Physiol. 2001;189:
257–265.
16. Turner RA, Pierce JG, du Vigneaud V. The purification and the amino
acid content of vasopressin preparations. J Biol Chem. 1951;191:21–28.
17. Hupf H, Grimm D, Riegger GA, Schunkert H. Evidence for a vasopressin
system in the rat heart. Circ Res. 1999;84:365–370.
18. Guillon G, Grazzini E, Andrez M, Breton C, Trueba M, Serradeil-LeGal
C, Boccara G, Derick S, Chouinard L, Gallo-Payet N. Vasopressin: a
potent autocrine/paracrine regulator of mammal adrenal functions.
Endocr Res. 1998;24:703–710.
19. Salzman AL, Vromen A, Denenberg A, Szabo C. K(ATP)-channel inhibition improves hemodynamics and cellular energetics in hemorrhagic
shock. Am J Physiol. 1997;272:H688 –H694.
20. Kusano E, Tian S, Umino T, Tetsuka T, Ando Y, Asano Y. Arginine
vasopressin inhibits interleukin-1 beta-stimulated nitric oxide and cyclic

guanosine monophosphate production via the V1 receptor in cultured rat
vascular smooth muscle cells. J Hypertens. 1997;15:627– 632.
21. Hamu Y, Kanmura Y, Tsuneyoshi I, Yoshimura N. The effects of vasopressin on endotoxin-induced attenuation of contractile responses in
human gastroepiploic arteries in vitro. Anesth Analg. 1999;88:542–548.
22. Hasenfuss G, Pieske B, Castell M, Kretschmann B, Maier LS, Just H.
Influence of the novel inotropic agent levosimendan on isometric tension
and calcium cycling in failing human myocardium. Circulation. 1998;98:
2141–2147.
23. Lehtonen L, Poder P. The utility of levosimendan in the treatment of heart
failure. Ann Med. 2007;39:2–17.
24. Mukae S, Yanagishita T, Geshi E, Umetsu K, Tomita M, Itoh S, Konno
N, Katagiri T. The effects of dopamine, dobutamine and amrinone on
mitochondrial function in cardiogenic shock. Jpn Heart J. 1997;38:
515–529.
25. Stamm C, Friehs I, Cowan DB, Cao-Danh H, Choi YH, Duebener LF,
McGowan FX, del Nido PJ. Dopamine treatment of postischemic contractile dysfunction rapidly induces calcium-dependent pro-apoptotic signaling. Circulation. 2002;106(suppl I):I-290 –I-298.
26. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M,
Hochman JS, Krumholz HM, Kushner FG, Lamas GA, Mullany CJ,
Ornato JP, Pearle DL, Sloan MA, Smith SC Jr, Alpert JS, Anderson JL,
Faxon DP, Fuster V, Gibbons RJ, Gregoratos G, Halperin JL, Hiratzka

27.

28.

29.
30.

31.

32.

33.

34.

35.

36.
37.

38.

39.

40.

41.

42.

1055

LF, Hunt SA, Jacobs AK, Ornato JP. ACC/AHA guidelines for the
management of patients with ST-elevation myocardial infarction: a report
of the American College of Cardiology/American Heart Association Task
Force on Practice Guidelines (Committee to Revise the 1999 Guidelines
for the Management of Patients With Acute Myocardial Infarction). J Am
Coll Cardiol. 2004;44:E1–E211.
Richard C, Ricome JL, Rimailho A, Bottineau G, Auzepy P. Combined

hemodynamic effects of dopamine and dobutamine in cardiogenic shock.
Circulation. 1983;67:620 – 626.
Lin H, Young DB. Opposing effects of plasma epinephrine and norepinephrine on coronary thrombosis in vivo. Circulation. 1995;91:
1135–1142.
Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl
J Med. 2001;345:588 –595.
Sharshar T, Carlier R, Blanchard A, Feydy A, Gray F, Paillard M,
Raphael JC, Gajdos P, Annane D. Depletion of neurohypophyseal content
of vasopressin in septic shock. Crit Care Med. 2002;30:497–500.
Landry DW, Levin HR, Gallant EM, Ashton RC Jr, Seo S, D’Alessandro
D, Oz MC, Oliver JA. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation. 1997;95:1122–1125.
Day TA, Randle JC, Renaud LP. Opposing alpha- and beta-adrenergic
mechanisms mediate dose-dependent actions of noradrenaline on
supraoptic vasopressin neurones in vivo. Brain Res. 1985;358:171–179.
Dunser MW, Mayr AJ, Ulmer H, Knotzer H, Sumann G, Pajk W,
Friesenecker B, Hasibeder WR. Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized, controlled study. Circulation.
2003;107:2313–2319.
Okamura T, Ayajiki K, Fujioka H, Toda N. Mechanisms underlying
arginine vasopressin-induced relaxation in monkey isolated coronary
arteries. J Hypertens. 1999;17:673– 678.
Jolly S, Newton G, Horlick E, Seidelin PH, Ross HJ, Husain M, Dzavik
V. Effect of vasopressin on hemodynamics in patients with refractory
cardiogenic shock complicating acute myocardial infarction.
Am J Cardiol. 2005;96:1617–1620.
Felker GM, O’Connor CM. Inotropic therapy for heart failure: an
evidence-based approach. Am Heart J. 2001;142:393– 401.
Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis
SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML, Mallis GI,
Sollano JA, Shannon J, Tandon PK, deMets DL; the PROMISE Study
Research Group. Effect of oral milrinone on mortality in severe chronic

heart failure. N Engl J Med. 1991;325:1468 –1475.
Stevenson LW. Clinical use of inotropic therapy for heart failure: looking
backward or forward? Part II: chronic inotropic therapy. Circulation.
2003;108:492– 497.
Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats
TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko
PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC Jr,
Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF,
Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B. ACC/AHA 2005
guideline update for the diagnosis and management of chronic heart
failure in the adult: a report of the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines (Writing
Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American
College of Chest Physicians and the International Society for Heart and Lung
Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;
112:e154–e235.
Thackray S, Easthaugh J, Freemantle N, Cleland JG. The effectiveness
and relative effectiveness of intravenous inotropic drugs acting through
the adrenergic pathway in patients with heart failure: a meta-regression
analysis. Eur J Heart Fail. 2002;4:515–529.
Nieminen MS, Bohm M, Cowie MR, Drexler H, Filippatos GS, Jondeau
G, Hasin Y, Lopez-Sendon J, Mebazaa A, Metra M, Rhodes A, Swedberg
K, Priori SG, Garcia MA, Blanc JJ, Budaj A, Cowie MR, Dean V,
Deckers J, Burgos EF, Lekakis J, Lindahl B, Mazzotta G, Morais J, Oto
A, Smiseth OA, Garcia MA, Dickstein K, Albuquerque A, Conthe P,
Crespo-Leiro M, Ferrari R, Follath F, Gavazzi A, Janssens U, Komajda
M, Morais J, Moreno R, Singer M, Singh S, Tendera M, Thygesen K.
Executive summary of the guidelines on the diagnosis and treatment of
acute heart failure: the Task Force on Acute Heart Failure of the European
Society of Cardiology. Eur Heart J. 2005;26:384 – 416.

Perrino C, Rockman HA, Chiariello M. Targeted inhibition of phosphoinositide 3-kinase activity as a novel strategy to normalize betaadrenergic receptor function in heart failure. Vascul Pharmacol. 2006;
45:77– 85.

Downloaded from by guest on July 10, 2014


1056

Circulation

September 2, 2008

43. Karlsberg RP, DeWood MA, DeMaria AN, Berk MR, Lasher KP;
Milrinone-Dobutamine Study Group. Comparative efficacy of short-term
intravenous infusions of milrinone and dobutamine in acute congestive
heart failure following acute myocardial infarction. Clin Cardiol. 1996;
19:21–30.
44. Aranda JM Jr, Schofield RS, Pauly DF, Cleeton TS, Walker TC, Monroe
VS Jr, Leach D, Lopez LM, Hill JA. Comparison of dobutamine versus
milrinone therapy in hospitalized patients awaiting cardiac transplantation: a prospective, randomized trial. Am Heart J. 2003;145:324 –329.
45. Moiseyev VS, Poder P, Andrejevs N, Ruda MY, Golikov AP, Lazebnik
LB, Kobalava ZD, Lehtonen LA, Laine T, Nieminen MS, Lie KI. Safety
and efficacy of a novel calcium sensitizer, levosimendan, in patients with
left ventricular failure due to an acute myocardial infarction: a randomized, placebo-controlled, double-blind study (RUSSLAN). Eur
Heart J. 2002;23:1422–1432.
46. Follath F, Cleland JG, Just H, Papp JG, Scholz H, Peuhkurinen K, Harjola
VP, Mitrovic V, Abdalla M, Sandell EP, Lehtonen L. Efficacy and safety
of intravenous levosimendan compared with dobutamine in severe lowoutput heart failure (the LIDO study): a randomised double-blind trial.
Lancet. 2002;360:196 –202.
47. Packer M. REVIVE II: multicentre placebo-controlled trial of levosimendan on clinical status in acutely decompensated heart failure. Presented at: 78th Scientific Sessions of the American Heart Association;

November 13–16, 2005; Dallas, Tex.
48. Mebazaa A, Nieminen MS, Packer M, Cohen-Solal A, Kleber FX, Pocock
SJ, Thakkar R, Padley RJ, Poder P, Kivikko M. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the
SURVIVE randomized trial. JAMA. 2007;297:1883–1891.
49. Hershberger RE, Nauman D, Walker TL, Dutton D, Burgess D. Care
processes and clinical outcomes of continuous outpatient support with
inotropes (COSI) in patients with refractory endstage heart failure. J Card
Fail. 2003;9:180 –187.
50. Fernandez-Gonzalez AL, Panizo-Santos A. Eosinophilic myocarditis in
heart transplant candidates. J Heart Lung Transplant. 1996;15:852– 853.
51. Sindone AP, Keogh AM, Macdonald PS, McCosker CJ, Kaan AF. Continuous home ambulatory intravenous inotropic drug therapy in severe
heart failure: safety and cost efficacy. Am Heart J. 1997;134:889 –900.
52. Stevenson LW, Massie BM, Francis GS. Optimizing therapy for complex
or refractory heart failure: a management algorithm. Am Heart J. 1998;
135:S293–S309.
53. 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2005;112(suppl
IV):IV-1–IV-203.
54. Paradis NA, Wenzel V, Southall J. Pressor drugs in the treatment of
cardiac arrest. Cardiol Clin. 2002;20:61–78, viii.
55. Gueugniaud PY, Mols P, Goldstein P, Pham E, Dubien PY, Deweerdt C,
Vergnion M, Petit P, Carli P; European Epinephrine Study Group. A
comparison of repeated high doses and repeated standard doses of epinephrine for cardiac arrest outside the hospital. N Engl J Med. 1998;339:
1595–1601.
56. Lindner KH, Strohmenger HU, Ensinger H, Hetzel WD, Ahnefeld FW,
Georgieff M. Stress hormone response during and after cardiopulmonary
resuscitation. Anesthesiology. 1992;77:662– 668.
57. Morris DC, Dereczyk BE, Grzybowski M, Martin GB, Rivers EP,
Wortsman J, Amico JA. Vasopressin can increase coronary perfusion
pressure during human cardiopulmonary resuscitation. Acad Emerg Med.
1997;4:878 – 883.

58. Wenzel V, Lindner KH, Prengel AW, Maier C, Voelckel W, Lurie KG,
Strohmenger HU. Vasopressin improves vital organ blood flow after
prolonged cardiac arrest with postcountershock pulseless electrical
activity in pigs. Crit Care Med. 1999;27:486 – 492.
59. Lindner KH, Dirks B, Strohmenger HU, Prengel AW, Lindner IM, Lurie
KG. Randomised comparison of epinephrine and vasopressin in patients
with out-of-hospital ventricular fibrillation. Lancet. 1997;349:535–537.
60. Wenzel V, Krismer AC, Arntz HR, Sitter H, Stadlbauer KH, Lindner KH.
A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med. 2004;350:105–113.

61. Kikura M, Sato S. The efficacy of preemptive milrinone or amrinone
therapy in patients undergoing coronary artery bypass grafting. Anesth
Analg. 2002;94:22–30.
62. Omae T, Kakihana Y, Mastunaga A, Tsuneyoshi I, Kawasaki K, Kanmura
Y, Sakata R. Hemodynamic changes during off-pump coronary artery
bypass anastomosis in patients with coexisting mitral regurgitation:
improvement with milrinone. Anesth Analg. 2005;101:2– 8.
63. Feneck RO, Sherry KM, Withington PS, Oduro-Dominah A. Comparison
of the hemodynamic effects of milrinone with dobutamine in patients
after cardiac surgery. J Cardiothorac Vasc Anesth. 2001;15:306 –315.
64. Byrne JG, Leacche M, Paul S, Mihaljevic T, Rawn JD, Shernan SK,
Mudge GH, Stevenson LW. Risk factors and outcomes for “vasoplegia
syndrome” following cardiac transplantation. Eur J Cardiothorac Surg.
2004;25:327–332.
65. Argenziano M, Chen JM, Choudhri AF, Cullinane S, Garfein E,
Weinberg AD, Smith CR Jr, Rose EA, Landry DW, Oz MC. Management
of vasodilatory shock after cardiac surgery: identification of predisposing
factors and use of a novel pressor agent. J Thorac Cardiovasc Surg.
1998;116:973–980.
66. Ozal E, Kuralay E, Yildirim V, Kilic S, Bolcal C, Kucukarslan N, Gunay

C, Demirkilic U, Tatar H. Preoperative methylene blue administration in
patients at high risk for vasoplegic syndrome during cardiac surgery. Ann
Thorac Surg. 2005;79:1615–1619.
67. Morales DL, Garrido MJ, Madigan JD, Helman DN, Faber J, Williams
MR, Landry DW, Oz MC. A double-blind randomized trial: prophylactic
vasopressin reduces hypotension after cardiopulmonary bypass. Ann
Thorac Surg. 2003;75:926 –930.
68. Dell’Italia LJ. Reperfusion for right ventricular infarction. N Engl J Med.
1998;338:978 –980.
69. Calvin JE Jr. Acute right heart failure: pathophysiology, recognition, and
pharmacological management. J Cardiothorac Vasc Anesth. 1991;5:
507–513.
70. Goldstein JA. Pathophysiology and management of right heart ischemia.
J Am Coll Cardiol. 2002;40:841– 853.
71. Ferrario M, Poli A, Previtali M, Lanzarini L, Fetiveau R, Diotallevi P,
Mussini A, Montemartini C. Hemodynamics of volume loading compared
with dobutamine in severe right ventricular infarction. Am J Cardiol.
1994;74:329 –333.
72. Marquez MF, Salica G, Hermosillo AG, Pastelin G, Cardenas M. Drug
therapy in Brugada syndrome. Curr Drug Targets Cardiovasc Haematol
Disord. 2005;5:409 – 417.
73. Summerhill EM, Baram M. Principles of pulmonary artery catheterization
in the critically ill. Lung. 2005;183:209 –219.
74. Shah MR, Hasselblad V, Stevenson LW, Binanay C, O’Connor CM,
Sopko G, Califf RM. Impact of the pulmonary artery catheter in critically
ill patients: meta-analysis of randomized clinical trials. JAMA. 2005;294:
1664 –1670.
75. Binanay C, Califf RM, Hasselblad V, O’Connor CM, Shah MR, Sopko G,
Stevenson LW, Francis GS, Leier CV, Miller LW. Evaluation study of
congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA. 2005;294:1625–1633.

76. Hayes MA, Timmins AC, Yau EH, Palazzo M, Hinds CJ, Watson D.
Elevation of systemic oxygen delivery in the treatment of critically ill
patients. N Engl J Med. 1994;330:1717–1722.
77. Alexander JH, Reynolds HR, Stebbins AL, Dzavik V, Harrington RA,
Van de Werf F, Hochman JS. Effect of tilarginine acetate in patients with
acute myocardial infarction and cardiogenic shock: the TRIUMPH randomized controlled trial. JAMA. 2007;297:1657–1666.
78. Dzavik V, Cotter G, Reynolds HR, Alexander JH, Ramanathan K,
Stebbins AL, Hathaway D, Farkouh ME, Ohman EM, Baran DA,
Prondzinsky R, Panza JA, Cantor WJ, Vered Z, Buller CE, Kleiman NS,
Webb JG, Holmes DR, Parrillo JE, Hazen SL, Gross SS, Harrington RA,
Hochman JS. Effect of nitric oxide synthase inhibition on haemodynamics and outcome of patients with persistent cardiogenic shock complicating acute myocardial infarction: a phase II dose-ranging study. Eur
Heart J. 2007;28:1109 –1116.
KEY WORDS: drugs
vasopressin

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heart failure

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inotropic agents

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shock

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